Mitochondrial longevity pathways.

Abstract

Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Better understanding of the underlying mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing oxidative damage. Reactive oxygen species (ROS) have been proposed to cause deleterious effects on DNA, proteins, and lipids, and generation of these highly reactive molecules takes place in the mitochondria. But ROS is positively implicated in cellular stress defense mechanisms and formation of ROS a highly regulated process controlled by a complex network of intracellular signaling pathways. There are endogenous anti-oxidant defense systems that have the potential to partially counteract ROS impact. In this review, we will describe pathways contributing to the regulation of the age-related decline in mitochondrial function and their impact on longevity. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.

A proton gradient is formed over the inner mitochondrial membrane by the respiratory chain. This proton gradient, achieved by oxidizing NADH and FADH2 from the TCA cycle, is crucial for complex IV to generate ATP from ADP + P. But during this process, single electrons generate superoxide by interacting with oxygen at complex I and III. The free radicals are then converted to oxygen and water by SOD1-2 and catalase. Uncoupling proteins in the mitochondrial innermembrane can decrease the proton gradient, and thereby decrease the ROS formation.

The free radical theory of aging: ROS formation leads to damaged mitochondrial DNA and proteins. The ROS induced damage reduces mitochondrial function and lifespan. This reduction in mitochondrial function with aging can be prevented by CR, and can prolong lifespan in several species.